Inhibitory nonsequence-specific effects of cytidine homopolymers on in vivo neointimal formation.
Phosphorothioate oligodeoxynucleotides (PS oligos) manifest both antisense and G-quartet aptameric inhibitory effects on vascular smooth muscle cell (SMC) proliferation. In this study, we examined the effects of three cytidine (S-dC) homopolymers lacking any guanosines of various chain length-S-dC28, S-dC18 and S-dC12-on in vitro SMC proliferation and in vivo neointimal formation. S-dC18 significantly inhibited human vascular SMC proliferation, although it had only half the potency as the same dose of S-dC28. Furthermore, S-dC12 at the same concentrations as S-dC18 did not significantly inhibit vascular SMC proliferation. S-dC28 and S-dC18 inhibited PDGF-induced in vitro SMC migration, whereas D-dC12 had no significant effect on PDGF-induced in vitro SMC migration. We determined the effects of S-dC28, S-dC18, and S-dC12 on neointimal SMC formation in the rat carotid balloon injury model. Rat carotid artery neointimal formation after balloon injury was significantly attenuated by S-dC28 treatment compared with the control group and by S-dC18 treatment compared with the control group. S-dC28 and S-dC18 treatment significantly reduced the intima/media area ratio compared with the values of the control groups. However, S-dC12 did not significantly inhibit neointimal formation. We investigated the time course of the inhibitory effects of S-dC28 on rat carotid artery neointimal formation. S-dC28 significantly inhibited rat carotid artery intimal area and intima/media area ratio at 4 weeks and 8 weeks. Fluoresceinated S-dC28 (FITC-S-dC28) was found to be present throughout the rat carotid arterial wall within 6 hours after balloon injury. Taken together, the potent non-G-quartet, nonsequence-specific inhibitory effects of S-dC compounds on in vitro SMC proliferation and in vivo neointimal formation in the rat carotid balloon injury model are chain length dependent and long lasting.
Wang
W
W
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Chen
H J
HJ
Schwartz
A
A
Cannon
P J
PJ
Stein
C A
CA
Rabbani
L E
LE
D000800:Angioplasty, Balloon; D000818:Animals; D001704:Biopolymers; D002339:Carotid Arteries / Q000166:cytology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003562:Cytidine / Q000737:chemistry / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D016650:Fluorescein-5-isothiocyanate; D006801:Humans; D051381:Rats
D001704:Biopolymers; D003562:Cytidine; D016650:Fluorescein-5-isothiocyanate